Li Rongkun, Ji Qian, Fu Shengqiao, Gu Jichun, Liu Dejun, Wang Lu, Yuan Xiao, Wen Yi, Dai Chunhua, Li Hengchao
Chest Oncology Department, Cancer Institute of Jiangsu University, Affiliated Hospital of Jiangsu University, Zhenjiang, 212001, China.
Department of Pulmonary Oncology, Zhongnan Hospital, Wuhan University, Wuhan, 430071, China.
Cancer Gene Ther. 2025 Feb;32(2):240-253. doi: 10.1038/s41417-024-00864-7. Epub 2024 Dec 17.
Pancreatic cancer is characterized by severe metabolic stress due to its prominent desmoplasia and poor vascularization. Integrin subunit alpha 3 (ITGA3) is a cell surface adhesion protein involved in tumor progression. However, the role of ITGA3 in pancreatic cancer progression, especially in metabolic reprogramming, remains largely unknown. In this study, we found that ITGA3 expression is elevated in pancreatic cancer tissues and predicts poor prognosis for patients with pancreatic cancer. Functional assays revealed that ITGA3 promotes the growth and liver metastasis of pancreatic cancer via boosting glycolysis. Mechanistically, Collagen I (Col1) derived from cancer cells acts as a ligand for ITGA3 to activate the FAK/PI3K/AKT/mTOR signaling pathway in an autocrine manner, thereby increasing the expression of HIF1α and c-Myc, two critical regulators of glycolysis. Blockade of Col1 by siRNA or of ITGA3 by a blocking antibody leads to specific inactivation of the FAK/PI3K/AKT/mTOR pathway and impairs malignant tumor behaviors induced by ITGA3. Thus, our data indicate that ITGA3 enhances glycolysis to promote pancreatic cancer growth and metastasis via increasing HIF1α and c-Myc expression in a Col1-dependent autocrine manner, making ITGA3 as a candidate diagnostic biomarker and a potential therapeutic target for pancreatic cancer.
胰腺癌的特征是由于其显著的促结缔组织增生和不良血管生成而导致严重的代谢应激。整合素亚基α3（ITGA3）是一种参与肿瘤进展的细胞表面粘附蛋白。然而，ITGA3在胰腺癌进展中的作用，尤其是在代谢重编程中的作用，在很大程度上仍不清楚。在本研究中，我们发现ITGA3在胰腺癌组织中表达升高，并预示着胰腺癌患者的预后不良。功能分析表明，ITGA3通过促进糖酵解来促进胰腺癌的生长和肝转移。机制上，癌细胞来源的I型胶原蛋白（Col1）作为ITGA3的配体，以自分泌方式激活FAK/PI3K/AKT/mTOR信号通路，从而增加糖酵解的两个关键调节因子HIF1α和c-Myc的表达。用siRNA阻断Col1或用阻断抗体阻断ITGA3会导致FAK/PI3K/AKT/mTOR通路的特异性失活，并损害ITGA3诱导的恶性肿瘤行为。因此，我们的数据表明，ITGA3通过以Col1依赖的自分泌方式增加HIF1α和c-Myc的表达来增强糖酵解，从而促进胰腺癌的生长和转移，使ITGA3成为胰腺癌的候选诊断生物标志物和潜在治疗靶点。
